Overexpression of the c-erb-2 oncogene (Her-2/neu) has been associated with poor clinical course in breast and ovarian cancers. c-erb-B-2 encodes a growth factor receptor with 50% homology to the EGF receptor, and multiple ligands have been recently described. Experiments in progress are determining the effect of c-erb-B-2 overexpression on the metastatic potential of human breast carcinoma cells. Transfection experiments have been performed to overexpress c-erb-B-2 in the human MDA-MB-435 breast carcinoma cell line at levels similar to those found in human tumors. Injection of control and c-erb-B-2 transfected cells into the mammary fat pads of nude mice has resulted in equivalent rates of metastasis to the regional lymph nodes, but significant differences in distant metastases. The c-erb-B-2 transfectants produced pulmonary metastases in 2-fold greater mice than did control transfectants. In contrast to the control transfected and parental cell lines, which typically contained one-several pulmonary metastases centered on capillaries, pathologic examination of lung sections from c-erb-B-2 transfectants revealed tens-hundreds of metastases in a proportion of animals. This "3+" metastatic pattern was five-fold more prevalent in the c-erb-B-2, than the control transfectants. The metastatic lesions also infiltrated the parenchyma of the lung extensively. In vitro studies in progress will determine the effect of c-erb-B-2 expression on cell growth, colonization, invasiveness and motility, both alone and in response to lung-derived factors and recombinant ligands. The experiments are expected to define a mechanism of action of the c-erb-B-2 oncogene, and may lead to therapeutic strategies.